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1.  Association of COPD with risk for pulmonary infections requiring hospitalization in HIV-infected Veterans 
Pulmonary infections remain more common in HIV-infected (HIV+) compared to uninfected individuals. The increase in chronic lung diseases among aging HIV+ individuals may contribute to this persistent risk. We sought to determine whether chronic obstructive pulmonary disease (COPD) is an independent risk factor for different pulmonary infections requiring hospitalization among HIV+ patients.
We analyzed data from 41,993 HIV+ Veterans in the nationwide Veterans Aging Cohort Study Virtual Cohort (VACS-VC) from 1996–2009. Using ICD-9 codes, we identified baseline comorbid conditions, including COPD, and incident community-acquired pneumonia (CAP), pulmonary tuberculosis (TB) and Pneumocystis jirovecii pneumonia (PCP) requiring hospitalization within two years after baseline. We used multivariable Poisson regression to determine incidence rate ratios (IRR) associated with COPD for each type of pulmonary infection, adjusting for comorbidities, CD4+ cell count, HIV viral load, smoking status, substance use, vaccinations and calendar year at baseline.
Unadjusted incidence rates of CAP, TB and PCP requiring hospitalization were significantly higher among persons with COPD compared to those without COPD (CAP: 53.9 vs. 19.4 per 1,000 person-years; TB: 8.7 vs. 2.8; PCP: 15.5 vs. 9.2; p ≤0.001). In multivariable Poisson regression models, COPD was independently associated with increased risk of CAP, TB and PCP (IRR 1.94, 95% CI 1.64–2.30; IRR 2.60, 95% CI 1.70–3.97; and IRR 1.48, 95% CI 1.10–2.01, respectively).
COPD is an independent risk factor for CAP, TB and PCP requiring hospitalization among HIV+ individuals. As the HIV+ population ages, the growing burden of COPD may confer substantial risk for pulmonary infections.
PMCID: PMC4607625  PMID: 26181820
COPD; pulmonary infection; pneumonia; HIV; comorbidities
2.  Depression and HIV Infection are Risk Factors for Incident Heart Failure Among Veterans: Veterans Aging Cohort Study 
Circulation  2015;132(17):1630-1638.
Both HIV and depression are associated with increased heart failure (HF) risk. Depression, a common comorbidity, may further increase the risk of HF among HIV+ adults. We assessed the association between HIV, depression and incident HF.
Methods and Results
Veterans Aging Cohort Study (VACS) participants free from cardiovascular disease at baseline (N = 81,427; 26,908 HIV+, 54,519 HIV-) were categorized into four groups: HIV- without major depressive disorder (MDD) [reference]; HIV- with MDD; HIV+ without MDD; and HIV+ with MDD. ICD-9 codes from medical records were used to determine MDD and the primary outcome, HF. After 5.8 follow-up years, HF rates per 1000 person-years were highest among HIV+ participants with MDD (9.32; 95% CI, 8.20–10.6). In Cox proportional hazards models, HIV+ participants with MDD had significantly higher risk of HF [adjusted hazard ratio (aHR) = 1.68; 95% CI, 1.45–1.95] compared to HIV- participants without MDD. MDD was associated with HF in separate fully adjusted models for HIV- and HIV+ participants (aHR = 1.21; 1.06–1.37 and 1.29; 1.11–1.51, respectively). Among those with MDD, baseline antidepressant use was associated with lower risk of incident HF events (aHR = 0.76; 0.58–0.99).
Our study is the first to suggest MDD is an independent risk factor for HF in HIV+ adults. These results reinforce the importance of identifying and managing MDD among HIV+ patients. Future studies must clarify mechanisms linking HIV, MDD, antidepressants, and HF; and identify interventions to reduce HF morbidity and mortality in those with both HIV and MDD.
PMCID: PMC4624488  PMID: 26358261
HIV infection; depression; psychiatric comorbidity; heart failure; epidemiology
3.  Thirty-Day Postoperative Mortality Among Individuals With HIV Infection Receiving Antiretroviral Therapy and Procedure-Matched, Uninfected Comparators 
JAMA surgery  2015;150(4):343-351.
Antiretroviral therapy (ART) has converted human immunodeficiency virus (HIV) infection into a chronic condition, and patients now undergo a variety of surgical procedures, but current surgical outcomes are inadequately characterized.
To compare 30-day postoperative mortality in patients with HIV infection receiving ART with the rates in uninfected individuals.
Retrospective analysis of nationwide electronic medical record data from the US Veterans Health Administration Healthcare System, October 1, 1996, to September 30, 2010. Common inpatient surgical procedures were grouped using the Healthcare Cost and Utilization Project Clinical Classification System to match HIV-infected and uninfected patients in a 1:2 ratio. Data on 1641 patients with HIV infection receiving combination ART who were undergoing inpatient surgery were compared with data on 3282 procedure-matched, uninfected comparators. Poisson regression models of 30-day postoperative mortality were adjusted for procedure year, age, Charlson Comorbidity Index score, hemoglobin level, albumin level, HIV infection, CD4 cell count, and HIV-1 RNA level.
All-cause 30-day postoperative mortality.
The most common procedures in both groups were cholecystectomy (10.5%), hip arthroplasty (10.5%), spine surgery (9.8%), herniorrhaphy (7.4%), and coronary artery bypass grafting (7.0%). In patients with HIV infection, CD4 cell distributions were 80.0% with 200/µL or more, 16.3% with 50/µL to 199/µL, and 3.7% with less than 50/µL; 74.1% of patients with HIV infection had undetectable HIV-1 RNA. Human immunodeficiency virus infection was associated with higher 30-day postoperative mortality compared with the mortality in uninfected patients (3.4% [56 patients]) vs 1.6% [53]); incidence rate ratio [IRR], 2.11; 95% CI, 1.41–3.17; P < .001). CD4 cell count was inversely associated with mortality, but HIV-1 RNA provided no additional information. After adjustment, patients with HIV infection had increased mortality compared with uninfected patients at all CD4 cell count strata (≥500/µL: IRR, 1.92; 95% CI, 1.02–3.60; P = .04; 200–499/µL: IRR, 1.89; 95% CI, 1.20–2.98; P = .01; 50–199/µL: IRR, 2.66; 95% CI, 1.29–5.47; P = .01; and <50/µL: IRR, 6.21; 95% CI, 3.55–10.85; P < .001). Hypoalbuminemia (IRR, 4.35; 95% CI, 2.78–6.81; P < .001) and age in decades (IRR, 1.47; 95% CI, 1.23–1.76; P < .001) were also strongly associated with mortality.
Current postoperative mortality rates among individuals with HIV infection who are receiving ART are low and are influenced as much by hypoalbuminemia and age as by CD4 cell status. Human immunodeficiency virus infection and CD4 cell count are only 2 of many factors associated with surgical outcomes that should be incorporated into surgical decision making.
PMCID: PMC5015449  PMID: 25714794
4.  Impact of Defined Clinical Population and Missing Data on Temporal Trends in HIV Viral Load Estimation within a Healthcare System 
HIV medicine  2015;16(6):346-354.
Community viral load (CVL) estimates vary based on analytic methods. We extended the CVL concept and used data from the Veterans Affairs Healthcare System (VA) to determine trends in the healthcare system viral load (HSVL), sensitivity to varying definitions of the clinical population, and assumptions regarding missing data.
We included HIV-infected patients in the Veterans Aging Cohort Study, 2000-2010, with >1 documented CD4 count, HIV-1 RNA or antiretroviral prescription (N=37,318). We created 6-month intervals including patients with ≥1 visit in the past 2 years. We assessed temporal trends in clinical population size, patient clinical status and mean HSVL and explored the impact of varying definitions of the clinical population and assumptions about missing viral load.
The clinical population size varied by definition, increasing from 16,000–19,000 patients in 2000 to 23,000–26,000 in 2010. The proportion of patients with suppressed HIV-1 RNA increased over time. Over 20% of patients had no viral load measured in a given interval or prior two years. Among patients with a current HIV-1 RNA, mean HSVL decreased from 97,800 in 2000 to 2,000 copies/mL in 2010. When current HIV-1 RNA data were unavailable and the HSVL was recalculated using the last available HIV-1 RNA, HSVL decreased from 322,300 to 9,900 copies/mL. HSVL was underestimated when using only current data in each interval.
The CVL concept can be applied to a healthcare system, providing a measure of healthcare quality. Like CVL, HSVL estimates depend on definitions of the clinical population and assumptions about missing data.
PMCID: PMC4478104  PMID: 25688937
HIV; community viral load; population surveillance; quality of health care; epidemiologic methods
5.  Do Biomarkers of Inflammation, Monocyte Activation, and Altered Coagulation Explain Excess Mortality Between HIV Infected and Uninfected People? 
Supplemental Digital Content is Available in the Text.
HIV infection and biomarkers of inflammation [measured by interleukin-6 (IL-6)], monocyte activation [soluble CD14 (sCD14)], and coagulation (D-dimer) are associated with morbidity and mortality. We hypothesized that these immunologic processes mediate (explain) some of the excess risk of mortality among HIV infected (HIV+) versus uninfected people independently of comorbid diseases.
Among 2350 (1521 HIV+) participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS BC), we investigated whether the association between HIV and mortality was altered by adjustment for IL-6, sCD14, and D-dimer, accounting for confounders. Participants were followed from date of blood draw for biomarker assays (baseline) until death or July 25, 2013. Analyses included ordered logistic regression and Cox Proportional Hazards regression.
During 6.9 years (median), 414 deaths occurred. The proportional odds of being in a higher quartile of IL-6, sCD14, or D-dimer were 2–3 fold higher for viremic HIV+ versus uninfected people. Mortality rates were higher among HIV+ compared with uninfected people [incidence rate ratio (95% CI): 1.31 (1.06 to 1.62)]. Mortality risk increased with increasing quartiles of IL-6, sCD14, and D-dimer regardless of HIV status. Adjustment for IL-6, sCD14, and D-dimer partially attenuated mortality risk among HIV+ people with unsuppressed viremia (HIV-1 RNA ≥10,000 copies per milliliter) compared with uninfected people—hazard ratio (95% CI) decreased from 2.18 (1.60 to 2.99) to 2.00 (1.45 to 2.76).
HIV infection is associated with elevated IL-6, sCD14, and D-dimer, which are in turn associated with mortality. Baseline measures of these biomarkers partially mediate excess mortality risk among HIV+ versus uninfected people.
PMCID: PMC4867134  PMID: 26885807
HIV; mortality; inflammation; monocyte activation; coagulation
6.  Prevalence and correlates of obstructive sleep apnea among patients with and without HIV infection 
HIV medicine  2014;16(2):105-113.
In HIV-uninfected populations, obstructive sleep apnea (OSA) is commonly associated with cardiovascular disease, metabolic syndrome, and cognitive impairment. These comorbidities are common in HIV-infected patients, but there are scarce data regarding OSA in HIV-infected patients. Therefore, we examined the prevalence and correlates of OSA in a cohort of HIV-infected and uninfected patients.
Observational cohort study.
Electronic medical record and self-report data were examined in patients enrolled in the Veterans Aging Cohort Study (VACS) between 2002-2008 and followed through 2010. The primary outcome was OSA diagnosis, determined using ICD-9 codes, in HIV-infected compared with uninfected. We used regression analyses to determine the association between OSA diagnosis, symptoms and comorbidities in adjusted models.
Of 3,683 HIV-infected and 3,641 uninfected patients, 143 (3.9%) and 453 (12.4%) had a diagnosis of OSA (p<0.0001), respectively. HIV-infected patients were more likely to report symptoms associated with sleep and OSA such as tiredness and fatigue. Compared with uninfected patients with OSA, HIV-infected patients with OSA were younger, had lower BMIs, and were less likely to have hypertension. In models adjusting for these traditional OSA risk factors, HIV infection was associated with markedly reduced odds of OSA diagnosis (odds ratio=0.48; 95% confidence interval 0.39—0.60).
HIV-infected patients are less likely to receive a diagnosis of OSA. Future studies are needed to determine whether the lower prevalence of OSA diagnoses in HIV-infected patients is due to decreased screening and detection or due to a truly decreased likelihood of OSA in the setting of HIV.
PMCID: PMC4300288  PMID: 25230851
HIV; Sleep apnea obstructive; Sleep apnea syndromes; Fatigue; Obesity
7.  Human immunodeficiency virus infection, cardiovascular risk factor profile and risk for acute myocardial infarction 
Traditional cardiovascular disease risk factors (CVDRFs) increase the risk of acute myocardial infarction (AMI) among HIV infected (HIV+) patients. We assessed the association between HIV and incident AMI within CVDRF strata.
81322 participants (33% HIV+) without prevalent CVD from the Veterans Aging Cohort Study-Virtual Cohort (prospective study of HIV+ and matched HIV− veterans). Veterans were followed from first clinical encounter on/after 4/1/2003 until AMI/death/last follow-up date (12/31/2009).
HIV, CVDRFs (total cholesterol, cholesterol-lowering agents, blood-pressure (BP), BP medication, smoking, diabetes) used to create 6 mutually exclusive profiles: all CVDRFs optimal, 1+ non-optimal CVDRFs, 1+ elevated CVDRFs, and 1, 2, 3+ major CVDRFs.
Incident AMI (defined using enzyme, EKG clinical data, 410 inpatient ICD-9 (Medicare), and/or death certificates). Statistics: Cox models adjusted for demographics, comorbidity, and substance use.
858 AMIs (42% HIV+) occurred over 5.9 years (median). Prevalence of optimal cardiac health was <2%. Optimal CVDRF profile was associated with the lowest adjusted AMI rates. Compared to HIV− veterans, AMI rates among HIV+ veterans with similar CVDRF profiles were higher. Compared to HIV− veterans without major CVDRFs, HIV+ veterans without major CVDRFs had a 2-fold increased risk of AMI (HR: 2.0 95%CI: 1.0–3.9, p=0.044).
The prevalence of optimal cardiac health is low in this cohort. Among those without major CVDRFs, HIV+ veterans have twice the AMI risk. Compared to HIV− veterans with high CVDRF burden, AMI rates were still higher in HIV+ veterans. Preventing/reducing CVDRF burden may reduce excess AMI risk among HIV+ people.
PMCID: PMC4441201  PMID: 25588033
HIV; optimal cardiovascular health; myocardial infarction
It is unknown whether smoking confers similar mortality risk in HIV-positive as in HIV-negative patients. We compared overall mortality stratified by HIV and smoking of 1,034 HIV-positive block-matched to 739 HIV-negative veterans, enrolled 2001–2002 in the Veterans Aging Cohort 5 Site Study. Adjusted incidence rate ratios (IRR) for mortality were calculated using Poisson regression. Mortality was significantly increased in HIV-positive veterans according to both smoking status and pack-years in unadjusted and adjusted analyses (adjusted IRR 2.31, 95% confidence interval [CI] 1.53–3.49 for HIV-positive current smokers and IRR 1.32, 95% CI 0.67–2.61 for HIV-negative current smokers). Comorbid diseases were also significantly increased according to smoking status and pack-years. Current smoking is associated with poor outcomes; even lower levels of exposure appear to be detrimental in HIV-infected veterans. These findings support the need for improvements in smoking cessation and for studies of mechanisms and diseases underlying increased mortality in smokers with HIV.
PMCID: PMC3118467  PMID: 19537953
9.  Disparities in Rates of Spine Surgery for Degenerative Spine Disease Between HIV Infected and Uninfected Veterans 
Spine  2012;37(7):612-622.
Study Design
Retrospective analysis of nationwide Veterans Health Administration (VA) clinical and administrative data.
Examine the association between HIV infection and the rate of spine surgery for degenerative spine disease.
Summary of Background Data
Combination anti-retroviral therapy (cART) has prolonged survival in patients with HIV/AIDS, increasing the prevalence of chronic conditions such as degenerative spine disease that may require spine surgery.
We studied all HIV infected patients under care in the VA from 1996–2008 (n=40,038) and uninfected comparator patients (n=79,039) matched on age, gender, race, year, and geographic region. The primary outcome was spine surgery for degenerative spine disease defined by ICD-9 procedure and diagnosis codes. We used a multivariate Poisson regression to model spine surgery rates by HIV infection status, adjusting for factors that might affect suitability for surgery (demographics, year, comorbidities, body mass index, cART, and laboratory values).
Two-hundred twenty eight HIV infected and 784 uninfected patients underwent spine surgery for degenerative spine disease during 700,731 patient-years of follow-up (1.44 surgeries per 1,000 patient-years). The most common procedures were spinal decompression (50%), and decompression and fusion (33%); the most common surgical sites were the lumbosacral (50%), and cervical (40%) spine. Adjusted rates of surgery were lower for HIV infected patients (0.86 per 1,000 patient-years of follow-up) than for uninfected patients (1.41 per 1,000 patient-years; IRR 0.61, 95% CI: 0.51, 0.74, P<0.001). Among HIV infected patients, there was a trend towards lower rates of spine surgery in patients with detectable viral loads levels (IRR 0.76, 95% CI: 0.55, 1.05, P=0.099).
In the VA, HIV infected patients experience significantly reduced rates of surgery for degenerative spine disease. Possible explanations include disease prevalence, emphasis on treatment of non-spine HIV-related symptoms, surgical referral patterns, impact of HIV on surgery risk-benefit ratio, patient preferences, and surgeon bias.
PMCID: PMC4507821  PMID: 21697770
disparities; HIV/AIDS; spine; surgery; outcomes
10.  Predicting Risk of End-Stage Liver Disease in Antiretroviral-Treated Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Patients 
Open Forum Infectious Diseases  2015;2(3):ofv109.
Background. End-stage liver disease (ESLD) is an important cause of morbidity among human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. Quantifying the risk of this outcome over time could help determine which coinfected patients should be targeted for risk factor modification and HCV treatment. We evaluated demographic, clinical, and laboratory variables to predict risk of ESLD in HIV/HCV-coinfected patients receiving antiretroviral therapy (ART).
Methods. We conducted a retrospective cohort study among 6016 HIV/HCV-coinfected patients who received ART within the Veterans Health Administration between 1997 and 2010. The main outcome was incident ESLD, defined by hepatic decompensation, hepatocellular carcinoma, or liver-related death. Cox regression was used to develop prognostic models based on baseline demographic, clinical, and laboratory variables, including FIB-4 and aspartate aminotransferase-to-platelet ratio index, previously validated markers of hepatic fibrosis. Model performance was assessed by discrimination and decision curve analysis.
Results. Among 6016 HIV/HCV patients, 532 (8.8%) developed ESLD over a median of 6.6 years. A model comprising FIB-4 and race had modest discrimination for ESLD (c-statistic, 0.73) and higher net benefit than alternative strategies of treating no or all coinfected patients at relevant risk thresholds. For FIB-4 >3.25, ESLD risk ranged from 7.9% at 1 year to 26.0% at 5 years among non-blacks and from 2.4% at 1 year to 14.0% at 5 years among blacks.
Conclusions. Race and FIB-4 provided important predictive information on ESLD risk among HIV/HCV patients. Estimating risk of ESLD using these variables could help direct HCV treatment decisions among HIV/HCV-coinfected patients.
PMCID: PMC4536329  PMID: 26284259
end-stage liver disease; hepatic decompensation; HIV; hepatitis C; HIV/HCV coinfection
11.  HIV Infection, Antiretroviral Therapy Initiation and Longitudinal Changes in Biomarkers of Organ Function§ 
Current HIV research  2014;12(1):50-59.
HIV is associated with end-organ diseases of aging via unclear mechanisms. Longitudinally assessing how HIV infection and ART initiation affect biomarkers of end organ function/disease could clarify these mechanisms. We investigated longitudinal changes in clinical biomarkers following 1) HIV infection and 2) ART initiation with evidence of viral suppression.
Cohort: Veterans Aging Cohort Study Virtual Cohort (VACS VC). VACS VC is a longitudinal cohort of HIV infected (HIV+) and race-ethnicity, sex, age, and clinical site-matched uninfected Veterans enrolled in the same calendar year. Inclusion criteria: a negative and successively positive (>six months) HIV antibody test. We used Wilcoxon signed-rank tests to analyze 1) the effect of HIV infection on lipids, renal, hepatic and hematologic/cardiovascular biomarkers and 2)whether ART initiation with HIV-1 RNA<500 cpm reverts any changes back to pre-HIV levels
422 Veterans had at least 1 biomarker measurement available prior to HIV infection and prior to ART initiation. 297 had at least 1 biomarker measurement available prior to HIV infection and after ART initiation with evidence of viral suppression. Mean age prior to HIV infection was 43 years. HIV infection was associated with reduction in total cholesterol, HDL cholesterol, LDL cholesterol, serum albumin, ALT, platelet count, hemoglobin and elevation of FIB-4 score and triglycerides. These changes occurred without significant changes in BMI. ART initiation (with HIV-1 RNA<500cpm) did not reverse alteration in triglycerides, LDL cholesterol, hemoglobin, or FIB-4 to pre-HIV infection levels.
HIV infection is associated with longitudinal changes in serum levels of several biomarkers of end-organ function/disease and mortality. Multiple biomarkers (triglycerides, LDL cholesterol, hemoglobin, and FIB-4) remain altered from levels prior to HIV infection levels even following inititiation of ART and evidence of viral suppression. These results give insights into underlying mechanisms of increased risk for aging-related chronic diseases in the context of HIV infection.
PMCID: PMC4495647  PMID: 25034208
Clinical biomarkers; chronic diseases of aging; HIV infection; lipids
12.  CD8+ T-Cells Count in Acute Myocardial Infarction in HIV Disease in a Predominantly Male Cohort 
BioMed Research International  2015;2015:246870.
Human Immunodeficiency Virus- (HIV-) infected persons have a higher risk for acute myocardial infarction (AMI) than HIV-uninfected persons. Earlier studies suggest that HIV viral load, CD4+ T-cell count, and antiretroviral therapy are associated with cardiovascular disease (CVD) risk. Whether CD8+ T-cell count is associated with CVD risk is not clear. We investigated the association between CD8+ T-cell count and incident AMI in a cohort of 73,398 people (of which 97.3% were men) enrolled in the U.S. Veterans Aging Cohort Study-Virtual Cohort (VACS-VC). Compared to uninfected people, HIV-infected people with high baseline CD8+ T-cell counts (>1065 cells/mm3) had increased AMI risk (adjusted HR = 1.82, P < 0.001, 95% CI: 1.46 to 2.28). There was evidence that the effect of CD8+ T-cell tertiles on AMI risk differed by CD4+ T-cell level: compared to uninfected people, HIV-infected people with CD4+ T-cell counts ≥200 cells/mm3 had increased AMI risk with high CD8+ T-cell count, while those with CD4+ T-cell counts <200 cells/mm3 had increased AMI risk with low CD8+ T-cell count. CD8+ T-cell counts may add additional AMI risk stratification information beyond that provided by CD4+ T-cell counts alone.
PMCID: PMC4320893  PMID: 25688354
13.  Medical ICU Admission Diagnoses and Outcomes in Human Immunodeficiency Virus–Infected and Virus–Uninfected Veterans in the Combination Antiretroviral Era 
Critical care medicine  2013;41(6):1458-1467.
Human immunodeficiency virus (HIV)–infected (HIV+) patients on combination antiretroviral therapy are living longer but have increased risk for aging-associated disease which may lead to increasing critical care requirements. We compare medical ICU admission characteristics and outcomes among HIV infected and demographically similar uninfected patients (uninfected) and considered whether an index which combines routine clinical biomarkers (the Veterans Aging Cohort Study Index) predicts 30-day medical ICU mortality.
Observational data analyses (Veterans Aging Cohort Study).
Eight Veterans Affairs medical centers nationwide.
HIV infected and uninfected with a medical ICU admission between 2002 and 2010.
Measurements and Main Results
Medical ICU admission was determined using bedsection (Veterans Affairs) and revenue center codes (Medicare). For Veterans Affairs admissions, we used clinical data to calculate Veterans Aging Cohort Study Index scores and multivariable logistic regression to determine factors associated with 30-day mortality. Overall, 539 of 3,620 (15%) HIV infected and 375 of 3,639 (10%) uninfected had a medical ICU admission; 72% and 78%, respectively, were Veterans Affairs based. HIV+ patients were younger at admission (p < 0.0001). Although most HIV+ patients were on antiretroviral therapy (71%) with undetectable HIV-1 RNA (54%), compared with uninfected they were more commonly admitted with respiratory diagnoses or infections (21% vs. 12%), were more likely to require mechanical ventilation (17% vs. 9%; p = 0.001), and had a higher mortality rate (18.6% vs. 11.2%, p = 0.003). Cardiovascular diagnoses were less common among HIV infected (18% vs. 29%; p < 0.0001). In logistic regression (c-statistic 0.87), a 5-point increment in Veterans Aging Cohort Study Index was associated with an odds ratio of death of 1.22 (95% confidence interval 1.14–1.30) among HIV infected and of 1.50 (95% confidence interval 1.29–1.76) among uninfected; infection/sepsis and respiratory diagnoses were also associated with mortality.
Medical ICU admission was frequent, 30-day mortality higher, and mechanical ventilation more common in HIV infected compared with uninfected. The Veterans Aging Cohort Study Index calculated at medical ICU admission predicted 30-day mortality for HIV infected and uninfected. As more individuals age with HIV, their requirements for medical ICU care may be greater than demographically similar uninfected individuals.
PMCID: PMC4283206  PMID: 23507717
30-day mortality; comorbidity; human immunodeficiency virus; medical ICU; Veterans Aging Cohort Study Index
14.  Prehypertension, Hypertension, and the Risk of Acute Myocardial Infarction in HIV-Infected and -Uninfected Veterans 
We found increased acute myocardial infarction risk among hypertensive and prehypertensive HIV-infected veterans compared to normotensive uninfected veterans, independent of confounding comorbidities.
Background. Compared to uninfected people, human immunodeficiency virus (HIV)–infected individuals may have an increased risk of acute myocardial infarction (AMI). Currently, HIV-infected people are treated to the same blood pressure (BP) goals (<140/90 or <130/80 mm Hg) as their uninfected counterparts. Whether HIV-infected people with elevated BP have excess AMI risk compared to uninfected people is not known. This study examines whether the association between elevated BP and AMI risk differs by HIV status.
Methods. The Veterans Aging Cohort Study Virtual Cohort (VACS VC) consists of HIV-infected and -uninfected veterans matched 1:2 on age, sex, race/ethnicity, and clinical site. For this analysis, we analyzed 81 026 people with available BP data from VACS VC, who were free of cardiovascular disease at baseline. BP was the average of the 3 routine outpatient clinical measurements performed closest to baseline (first clinical visit after April 2003). BP categories used in the analyses were based on criteria of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Analyses were performed using Cox proportional hazards regression.
Results. Over 5.9 years (median), 860 incident AMIs occurred. Low/high prehypertensive and untreated/treated hypertensive HIV-infected individuals had increased AMI risk compared to uninfected, untreated normotensive individuals (hazard ratio [HR], 1.60 [95% confidence interval {CI}, 1.07–2.39]; HR, 1.81 [95% CI, 1.22–2.68]; HR, 2.57 [95% CI, 1.76–3.76]; and HR, 2.76 [95% CI, 1.90–4.02], respectively).
Conclusions. HIV, prehypertensive BP, and hypertensive BP were associated with an increased risk of AMI in a cohort of HIV-infected and -uninfected veterans. Future studies should prospectively investigate whether HIV interacts with BP to further increase AMI risk.
PMCID: PMC3864500  PMID: 24065316
blood pressure; prehypertension; HIV; myocardial infarction
15.  Hepatic Decompensation in Antiretroviral-Treated HIV/Hepatitis C-Coinfected Compared to Hepatitis C-Monoinfected Patients: A Cohort Study 
Annals of internal medicine  2014;160(6):369-379.
The incidence and determinants of hepatic decompensation have been incompletely examined among HIV/hepatitis C virus (HCV)-coinfected patients in the antiretroviral therapy (ART) era, and few studies have compared rates of outcomes to those of patients with chronic HCV alone.
To compare the incidence of hepatic decompensation between antiretroviral-treated HIV/HCV-coinfected and HCV-monoinfected patients, and evaluate factors associated with decompensation among coinfected patients on ART.
Retrospective cohort study.
Veterans Health Administration.
4,280 HIV/HCV-coinfected patients who initiated ART and 6,079 HCV-monoinfected patients receiving care between 1997 and 2010. All patients had detectable HCV RNA and were HCV treatment-naïve.
Incident hepatic decompensation, determined by diagnoses of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage.
The incidence of hepatic decompensation was greater among coinfected than monoinfected patients (at 10 years: 7.4% versus 4.8%; p<0.001). Compared to HCV-monoinfected patients, antiretroviral-treated HIV/HCV-coinfected patients had a higher rate of hepatic decompensation (hazard ratio [HR] accounting for competing risks, 1.56 [95% confidence interval (CI), 1.31–1.86]). Coinfected patients who maintained HIV RNA levels <1,000 copies/mL still had higher rates of decompensation than HCV-monoinfected patients (HR, 1.44 [95% CI, 1.05–1.99]). Baseline advanced hepatic fibrosis (FIB-4 >3.25; HR, 5.45 [95% CI, 3.79–7.84]), baseline hemoglobin <10 g/dL (HR, 2.24 [CI, 1.20–4.20]), diabetes mellitus (HR, 1.88[95% CI, 1.38–2.56]), and non-black race (HR, 2.12 [95% CI, 1.65–2.72]) were each associated with higher rates of decompensation among coinfected patients on ART.
Observational study of predominantly male patients.
Despite ART, HIV/HCV-coinfected patients had higher rates of hepatic decompensation than HCV-monoinfected individuals. Rates of decompensation were higher for coinfected patients with advanced liver fibrosis, severe anemia, diabetes, and non-black race.
PMCID: PMC4254786  PMID: 24723077
hepatic decompensation; end-stage liver disease; HIV/HCV coinfection; HIV; hepatitis C
16.  Risk factors for hospitalization and medical intensive care unit (MICU) admission among HIV infected Veterans 
With improved survival of HIV-infected persons on antiretroviral therapy and growing prevalence of non-AIDS diseases, we asked whether the VACS Index, a composite measure of HIV-associated and general organ dysfunction predictive of all-cause mortality, predicts hospitalization and medical intensive care unit (MICU) admission. We also asked whether AIDS and non-AIDS conditions increased risk after accounting for VACS Index score.
We analyzed data from the Veterans Aging Cohort Study (VACS), a prospective study of HIV-infected Veterans receiving care between 2002–2008. Data were obtained from the electronic medical record, VA administrative databases and patient questionnaires, and were used to identify comorbidities and calculate baseline VACS Index scores. The primary outcome was first hospitalization within 2 years of VACS enrollment. We used multivariable Cox regression to determine risk factors associated with hospitalization and logistic regression to determine risk factors for MICU admission, given hospitalization.
1141/3410 (33.5%) patients were hospitalized within 2 years; 203/1141 (17.8%) included a MICU admission. Median VACS Index scores were 25 (no hospitalization), 34 (hospitalization only) and 51 (MICU). In adjusted analyses, a 5-point increment in VACS Index score was associated with 10% higher risk of hospitalization and MICU admission. In addition to VACS Index score, Hispanic ethnicity, current smoking, hazardous alcohol use, chronic obstructive pulmonary disease, hypertension, diabetes and prior AIDS-defining event predicted hospitalization. Among those hospitalized, VACS Index score, cardiac disease and prior cancer predicted MICU admission.
The VACS Index predicted hospitalization and MICU admission as did current smoking, hazardous alcohol use, and AIDS and certain non-AIDS diagnoses.
PMCID: PMC4182723  PMID: 23111572
HIV; hospitalization; medical intensive care unit (MICU); aging; VACS Index; comorbidity
17.  Unhealthy Alcohol and Illicit Drug Use are Associated with Decreased Quality of HIV Care 
HIV-infected patients with substance use experience suboptimal health outcomes, possibly to due to variations in care.
To assess the association between substance use and the quality of HIV care (QOC) received.
Research Design
Retrospective cohort study.
HIV-infected patients enrolled in the Veterans Aging Cohort Study.
We collected self-report substance use data and abstracted 9 HIV quality indicators (QIs) from medical records. Independent variables were unhealthy alcohol use (AUDIT-C score ≥4) and illicit drug use (self-report of stimulants, opioids, or injection drug use in past year). Main outcome was the percentage of QIs received, if eligible. We estimated associations between substance use and QOC using multivariable linear regression.
The majority of the 3,410 patients were male (97.4%) and Black (67.0%) with a mean age of 49.1 years (SD 8.8). Overall, 25.8% reported unhealthy alcohol use, 22% illicit drug use, and participants received 81.5% (SD=18.9) of QIs. The mean percentage of QIs received was lower for those with unhealthy alcohol use vs. not (59.3% vs. 70.0%, p<.001) and those using illicit drugs vs. not (57.8% vs. 70.7%, p<.001). In multivariable models, unhealthy alcohol use (adjusted β −2.74; 95% CI −4.23, −1.25) and illicit drug use (adjusted β −3.51 95% CI −4.99, −2.02) remained inversely associated with the percentage of QIs received.
Though the overall QOC for these HIV-infected Veteran patients was high, gaps persist for those with unhealthy alcohol and illicit drug use. Interventions that address substance use in HIV-infected patients may improve the QOC received.
PMCID: PMC3460799  PMID: 22820808
Alcohol; Quality of Health Care; HIV; Quality Indicators; Health Care; Opioid-Related Disorders
18.  Comorbid diabetes and the risk of progressive chronic kidney disease in HIV-infected adults: Data from the Veterans Aging Cohort Study 
Approximately 15% of HIV-infected individuals have comorbid diabetes. Studies suggest that HIV and diabetes have an additive effect on chronic kidney (CKD) progression; however, this observation may be confounded by differences in traditional CKD risk factors.
We studied a national cohort of HIV-infected and matched HIV-uninfected individuals who received care through the Veterans Healthcare Administration. Subjects were divided into four groups based on baseline HIV and diabetes status, and the rate of progression to an estimated glomerular filtration rate (eGFR) < 45ml/min/1.73m2 was compared using Cox-proportional hazards modeling to adjust for CKD risk factors.
31,072 veterans with baseline eGFR ≥ 45ml/min/1.73m2 (10,626 with HIV only, 5,088 with diabetes only, and 1,796 with both) were followed for a median of 5 years. Mean baseline eGFR was 94ml/min/1.73m2, and 7% progressed to an eGFR < 45ml/min/1.73m2. Compared to those without HIV or diabetes, the relative rate of progression was increased in individuals with diabetes only [adjusted hazard ratio (HR) 2.48; 95% confidence interval (CI) 2.19–2.80], HIV only [HR 2.80, 95% CI 2.50–3.15], and both HIV and diabetes [HR 4.47, 95% CI 3.87–5.17].
Compared to patients with only HIV or diabetes, patients with both diagnoses are at significantly increased risk of progressive CKD even after adjusting for traditional CKD risk factors. Future studies should evaluate the relative contribution of complex comorbidities and accompanying polypharmacy to the risk of CKD in HIV-infected individuals, and prospectively investigate the use of cART, glycemic control, and adjunctive therapy to delay CKD progression.
PMCID: PMC3392432  PMID: 22592587
non-AIDS complications; HIV; chronic kidney disease; diabetes; risk factors
19.  Sex Disparities in Overall Burden of Disease Among HIV-Infected Individuals in the Veterans Affairs Healthcare System 
Journal of General Internal Medicine  2013;28(Suppl 2):577-582.
Whether sex disparities exist in overall burden of disease among human immunodeficiency virus (HIV)-infected individuals in the Veterans Affairs healthcare system (VA) is unknown.
To determine whether sex differences exist in overall burden of disease after 1 year of combined antiretroviral therapy (ART) among HIV-infected individuals in VA.
Retrospective cohort study.
Among patients in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC), all ART-naïve HIV-infected Veterans who received VA-based HIV care between 1996 and 2009.
Overall burden of disease was measured using the VACS Index, an index that incorporates HIV (e.g. CD4 cell count) and non-HIV biomarkers (e.g. hemoglobin) and is highly predictive of all-cause mortality. Possible scores range from 0 to 164, although scores typically range from 0 to 50 for 80 % of patients in VACS-VC. A higher score indicates greater burden of disease (each additional five points indicates approximately 20 % increased 5-year mortality risk). ART adherence was measured using pharmacy data.
Complete data were available for 227 women and 8,073 men. At ART initiation, compared with men, women were younger and more likely to be Black, less likely to have liver dysfunction, but more likely to have lower hemoglobin levels. Median VACS Index scores changed from ART initiation to 1 year after ART initiation: women’s scores went from 41 to 28 for women (13 point improvement) and men’s from 42 to 27 for men (15 point improvement). In multivariable regression, women had 3.6 point worse scores than men after 1 year on ART (p = 0.002); this difference decreased to 3.2 points after adjusting for adherence (p = 0.004).
In VA, compared to men, women experienced less improvement in overall burden of disease after 1 year of HIV treatment. Further study is needed to elucidate the modifiable factors that may explain this disparity.
PMCID: PMC3695278  PMID: 23807068
women; Veterans; HIV; health care disparities; burden of illness
20.  Risk of Heart Failure With Human Immunodeficiency Virus in the Absence of Prior Diagnosis of Coronary Heart Disease 
Archives of internal medicine  2011;171(8):737-743.
Whether human immunodeficiency virus (HIV) infection is a risk factor for heart failure (HF) is not clear. The presence of coronary heart disease and alcohol consumption in this population may confound this association.
To determine whether HIV infection is a risk factor for incident HF, we conducted a population-based, retrospective cohort study of HIV-infected and HIV-uninfected veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC) and the 1999 Large Health Study of Veteran Enrollees (LHS) from January 1, 2000, to July 31, 2007.
There were 8486 participants (28.2% HIV-infected) enrolled in the VACS-VC who also participated in the 1999 LHS. During the median 7.3 years of follow-up, 286 incident HF events occurred. Age- and race/ethnicity–adjusted HF rates among HIV-infected and HIV-uninfected veterans were 7.12 (95% confidence interval [CI],6.90-7.34) and 4.82 (95% CI, 4.72-4.91) per 1000 person-years, respectively. Compared with HIV-uninfected veterans, those who were HIV infected had an increased risk ofHF (adjusted hazard ratio [HR], 1.81; 95% CI, 1.39-2.36). This association persisted among veterans who did not have a coronary heart disease event or a diagnosis related to alcohol abuse or dependence before the incident HF event (adjusted HR, 1.96; 95% CI, 1.29-2.98). Compared with HIV-uninfected veterans, those who were HIV infected with a baseline Human immunodeficiency virus 1 (HIV-1) RNA level of 500 or more copies/mL had a higher risk of HF (adjusted HR, 2.28; 95% CI, 1.57-3.32), while those with baseline and a recent HIV-1 RNA level less than 500 copies/mL did not (adjusted HR, 1.10; 95% CI, 0.64-1.89; P< .001 for comparison between high and low HIV-1 RNA groups).
Our data suggest that HIV infection is a risk factor for HF. Ongoing viral replication is associated with a higher risk of developing HF.
PMCID: PMC3687533  PMID: 21518940
21.  Validating Smoking Data From the Veteran’s Affairs Health Factors Dataset, an Electronic Data Source 
Nicotine & Tobacco Research  2011;13(12):1233-1239.
We assessed smoking data from the Veterans Health Administration (VHA) electronic medical record (EMR) Health Factors dataset.
To assess the validity of the EMR Health Factors smoking data, we first created an algorithm to convert text entries into a 3-category smoking variable (never, former, and current). We compared this EMR smoking variable to 2 different sources of patient self-reported smoking survey data: (a) 6,816 HIV-infected and -uninfected participants in the 8-site Veterans Aging Cohort Study (VACS-8) and (b) a subset of 13,689 participants from the national VACS Virtual Cohort (VACS-VC), who also completed the 1999 Large Health Study (LHS) survey. Sensitivity, specificity, and kappa statistics were used to evaluate agreement of EMR Health Factors smoking data with self-report smoking data.
For the EMR Health Factors and VACS-8 comparison of current, former, and never smoking categories, the kappa statistic was .66. For EMR Health Factors and VACS-VC/LHS comparison of smoking, the kappa statistic was .61.
Based on kappa statistics, agreement between the EMR Health Factors and survey sources is substantial. Identification of current smokers nationally within the VHA can be used in future studies to track smoking status over time, to evaluate smoking interventions, and to adjust for smoking status in research. Our methodology may provide insights for other organizations seeking to use EMR data for accurate determination of smoking status.
PMCID: PMC3223583  PMID: 21911825
22.  Food Insecurity is Associated with Poor Virologic Response among HIV-Infected Patients Receiving Antiretroviral Medications 
Journal of General Internal Medicine  2011;26(9):1012-1018.
Food insecurity negatively impacts HIV disease outcomes in international settings. No large scale U.S. studies have investigated the association between food insecurity and severity of HIV disease or the mechanism of this possible association. The objective of this study was to examine the impact of food insecurity on HIV disease outcomes in a large cohort of HIV-infected patients receiving antiretroviral medications.
This is a cross-sectional study.
Participants were HIV-infected patients enrolled in the Veterans Aging Cohort Study between 2002–2008 who were receiving antiretroviral medications.
Participants reporting “concern about having enough food for you or your family in the past 30 days” were defined as food insecure. Using multivariable logistic regression, we explored the association between food insecurity and both low CD4 counts (<200 cells/μL) and unsuppressed HIV-1 RNA (>500 copies/mL). We then performed mediation analysis to examine whether antiretroviral adherence or body mass index mediates the observed associations.
Among 2353 HIV-infected participants receiving antiretroviral medications, 24% reported food insecurity. In adjusted analyses, food insecure participants were more likely to have an unsuppressed HIV-1 RNA (AOR 1.37, 95% CI 1.09, 1.73) compared to food secure participants. Mediation analysis revealed that neither antiretroviral medication adherence nor body mass index contributes to the association between food insecurity and unsuppressed HIV-1 RNA. Food insecurity was not independently associated with low CD4 counts.
Among HIV-infected participants receiving antiretroviral medications, food insecurity is associated with unsuppressed viral load and may render treatment less effective. Longitudinal studies are needed to test the potential causal association between food insecurity, lack of virologic suppression, and additional HIV outcomes.
PMCID: PMC3157515  PMID: 21573882
food insecurity; HIV; patients; antiretrovirals
23.  Validity of Diagnostic Codes and Liver-Related Laboratory Abnormalities to Identify Hepatic Decompensation Events in the Veterans Aging Cohort Study 
The absence of validated methods to identify hepatic decompensation in cohort studies has prevented a full understanding of the natural history of chronic liver diseases and impact of medications on this outcome. We determined the ability of diagnostic codes and liver-related laboratory abnormalities to identify hepatic decompensation events within the Veterans Aging Cohort Study (VACS).
Medical records of patients with hepatic decompensation codes and/or laboratory abnormalities of liver dysfunction (total bilirubin ≥5.0 gm/dL, albumin ≤2.0 gm/dL, international normalized ratio ≥1.7) recorded one year before through six months after VACS entry were reviewed to identify decompensation events (i.e., ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, hepatocellular carcinoma) at VACS enrollment. Positive predictive values (PPVs) of diagnostic codes, laboratory abnormalities, and their combinations for confirmed outcomes were determined.
Among 137 patients with a hepatic decompensation code and 197 with a laboratory abnormality, the diagnosis was confirmed in 57 (PPV, 42%; 95% CI, 33% – 50%) and 56 (PPV, 28%; 95% CI, 22% – 35%), respectively. The combination of any code plus laboratory abnormality increased PPV (64%; 95% CI, 47% - 79%). One inpatient or ≥2 outpatient diagnostic codes for ascites, spontaneous bacterial peritonitis, or variceal hemorrhage had high PPV (91%; 95% CI, 77% – 98%) for confirmed hepatic decompensation events.
An algorithm of 1 inpatient or ≥2 outpatient codes for ascites, peritonitis, or variceal hemorrhage has sufficiently high PPV for hepatic decompensation to enable its use for epidemiologic research in VACS. This algorithm may be applicable to other cohorts.
PMCID: PMC3131229  PMID: 21626605
hepatic decompensation; end-stage liver disease; epidemiologic methods; outcomes; validation studies
24.  HIV Infection and Risk for Incident Pulmonary Diseases in the Combination Antiretroviral Therapy Era 
Rationale: In aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality. Pulmonary diseases have not been systematically assessed in the combination antiretroviral therapy (ART) era.
Objectives: To determine the incidence of pulmonary diseases in HIV-infected persons compared with HIV-uninfected persons.
Methods: We analyzed data from the Veterans Aging Cohort Study Virtual Cohort, consisting of 33,420 HIV-infected veterans and 66,840 age, sex, race and ethnicity, and site-matched HIV-uninfected veterans. Using Poisson regression, incidence rates and adjusted incidence rate ratios were calculated to determine the association of HIV with pulmonary disease. The Virtual Cohort was merged with the 1999 Veterans Large Health Survey to adjust for self-reported smoking in a nested sample (14%).
Measurements and Main Results: Incident chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis, as well as pulmonary infections, were significantly more likely among HIV-infected patients compared with uninfected patients in adjusted analyses, although rates of asthma did not differ by HIV status. Bacterial pneumonia and chronic obstructive pulmonary disease were the two most common incident pulmonary diseases, whereas opportunistic pneumonias were less common. Absolute rates of most pulmonary diseases increased with age, although the relative differences between those with and without HIV infection were greatest in younger persons. Chronic obstructive pulmonary disease and asthma, as well as pulmonary infections, were less likely in those with lower HIV RNA levels and use of ART at baseline.
Conclusions: Pulmonary diseases among HIV-infected patients receiving care within the Veterans Affairs Healthcare System in the combination ART era reflect a substantial burden of non–AIDS-defining and chronic conditions, many of which are associated with aging.
PMCID: PMC3266024  PMID: 20851926
HIV; respiratory tract diseases; lung diseases, obstructive; pneumonia; pneumonia, bacterial

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